21-amino-3 beta, 20-dihydroxy-allopregnanes



3,074,933 21-AMlN0-3,B,20-DIHYDROXY-ALLOPREGNANES Fred A. Kincl, Mexico City, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation of Panama 14, 1962, Ser. No. 173,133

No Drawing. Filed Feb.

Claims. (Cl.

R1 CHr-CH N H 23 NW OR In the above formula, R represents hydrogen or the acyl residue of a hydrocarbon carboxylic acid containing less than 12 carbon atoms. R and R each represent hydrogen, alkyl, aryl, aralkyl or dialkylaminoalkyl groups having from 1 to 8 carbon atoms; R and R together with the nitrogen atom may also represent a heterocyclic radical such as piperidyl, morpholyl, pyrrolidyl or piperazyl, which may or may not be substituted with a lower alkyl radical. The wavy line at C2() indicates the a or B configuration for the hydroxy (acyloxy) group in such position.

The present invention also comprises the inorganic and organic salts formed by treatment of the amino compounds with acids, such as for example hydrochloric, hydrobromic, sulfuric, phosphoric, tartaric or ethylsulfonic acid.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and B-chloropropionate.

The compounds object of the present invention are bacteriostatic agents active against gram positive bacteria, such as Staphylococcus aureus and Mycobacterium tuberculosis. They are also useful as stimulants of the central nervous system.

The salts are water soluble and may therefore be used with advantage in aqueous solution.

The compounds object of the present invention are obtained by treating allopregnanolone with formaldehyde and an amine under appropriate conditions, followed by reduction at C-ZO with a double metal hydride and esterification of the hydroxyl groups.

tates atent 3,9743% Patented Jan. 22, 1953 "ice In the above formulas R, R and R have the same meaning as heretofore set forth; X represents an anion residue of the previously mentioned acids.

In practicing the process outlined above, allopregnan- 3f3-ol-2 0-one (I) is subjected to a Mannich type condensation by treatment with paraformaldehyde and an amine hydrochloride, in an inert organic solvent, preferably using isoamyl or teramyl alcohols as solvent. The reaction is effected at reflux temperature and for a period of time in the order of 1 to 6 hours.

There can be used for this reaction the hydrochlorides of a great variety of amines: aliphatic primary or secondary amines such as dimethylamine, diethylamine, methyl ethylamine or the like; aromatic amines such as benzylamine, methyl aniline, phenethylamine or heterocyclic amines, such as for example piperidine, piperazine, morpholine, pyrrolidine etc., to give the corresponding 21-aminoallopregnanes (ll).

Upon treatment of these ZI-amino compounds with a double metal hydride, such as lithium aluminum hydride or sodium borohydride, the ZO-keto group is reduced to give a mixture of the 20mand ZOB-alcohols, predominating the B-isomer (III:R=H) which can be separated by the ordinary methods, preferably by chromatography or crystallization.

The 21-amino-3p,20;8-dihydroxy allopregnanes thus obtained are esterified by conventional methods with acid anhydrides or chlorides in pyridine solution to give the corresponding diesters (lIIzR: acyl).

If so desired, the amines may be converted into the inorganic or organic salts (IV), for example, by treatment with hydrochloric, sulfuric, phosphoric, tartaric acid etc. in ether solution.

Z13 the following examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I methyl) allopregnan-iB-ol-ZO-one.

A solution of =1 g. of sodium borohydride in 3 cc. of water was added .to an ice-cooled solution of 1 g. of the above compound in 120 cc.

The product Was extracted with ethyl acetate, the extract was washed with Water, dried and evaporated. The solid residue, consisting of a mixture of 200a and Ztlti-h-ydroxy compounds, was purified by crystallization from acetone-hexane to give the 2l-(N,N- dimethylamino methyl)allopregnane-3/3,20 3-diol, with M.-P. 96-102 C.

Example II Into a solution of 1 g. of ZI-methyl ('N,N-dimethylamino) allopregnan-3B,2OB-diol in 50 cc. of anhydrous ether, there was passed a slow stream of anhydrous hydrogen chloride, for 1 hour. The white precipitate formed was collected by filtration, washed with anhydrous ether zation from acetone-hexane, thus methyl-allopregnane-3,8,20;B-diol.

Example V chloride; there was thus produced 2l-(N-methylanilinomethyl)allopregnan-3fl-ol-20-one, which after reduction with sodium borohydride in methanol solution, gave 21- methyl-anilino-rnethyl-allopregnane-3fl,20,B-diol in mixture with the 20a-isomer.

Example VI To a solution of 500 mg. of 2l-methyl anilinomethylallopregnane-3fl,20fi-diol in 35 cc. of anhydrous ether, there was added a mixture of anhydrous ether containing obtained the pure sulfate of 21-methylanilino methyl-allopregnane-3,6,2OB-diol.

In another experiment, the sulfuric acid was substituted by phosphoric acid, to give the corresponding phosphate.

Example VII A solution of 2 g. of 2.1-piperidinomethyl-allopregnane- 3fi,20,8-diol in 50 cc. of anhydrous methanol was treated with 1 g. of tartaric acid, and the mixture kept at room temperature for 24 hours. The white precipitate formed was separated by filtration and recrystallized from ethanol, thus affording the tartrate of ZI-piperid-inomethyl-allopregnane-filLZOfl-diol.

In a similar manner, 2l-methyl ('N,N dimethylamino) allopregnane-3;9,20fl-diol was converted into the corresponding tartrate.

Example VIII Example IV was repeated, but using pyrrolidine hydrochloride instead of piperidine hydrochloride, thus producing 21-pyrrolidinomethyl-allopregnan-3fi-ol 20 one and 2.1-pyrrolidinomethyl-allopregnane-3B,2OB-d.iol. A mixture of 500 mg. of the latter compound, 2 cc. of cyclopentylpropionic 'anhydride and 2 cc. of pyridine was kept at room temperature overnight. It was poured into water, extracted with methylene chloride and the organic extract washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone hexane gave 2.1-pyrrolidinomethyl=allopregnane- 3,8,20fl-diol-dicyclopentylpropionate.

Upon treatment of the above compound with hydrogen chloride in anhydrous ether, there was obtained the corresponding chlorohydrate.

Example IX Example X methyl (N,N-dimethylamino) By the same method, 2l-piperidinomethyl-allopregnane- 313,20fi-diol, ZI-pyrrolidino methyl-allopregnane-3fi,20,6- diol and 21-morpholinomethyl-allopregnane3fl,20 -diol were converted into the corresponding diacetates.

- manner, but using caproic, valeric and undecenoic anhydrides as esterifying agents, there were produced the dicaproate, divalerate and diundecenoates of such compounds.

allopregnane-3B,20,8-diol.

Example XI Example IX was repeated, but using piperazine hydrochloride, instead of morpholine hydrochloride. There were thus obtained 2'1-piperazinomethyl-allopregnan-3fiol-20-one and 21-piperazinomethyl-allopregnane-B6,205- diol.

' Esterification of the latter compound with propionic anhydride, by following the method of Example III, gave the dipropionate of 2l-piperazinomethyl-allopregnane- 35,205-diol.

The above compound was then converted into the corresponding sulfate by treatment with sulfuric acid in ether, in accordance with the methoddescribed in Example VI.

1 claim:

1. A compound selected from the group consisting ofthose of the following formula:

R1 CHr-GHr-N HN R and the water soluble acid salts thereof; wherein R is selected from the group consisting of hydrogen and a hydrocarbon acyl radical of less than 12 carbon atoms; R and R are selected from the group consisting of hydrogen, allgyl, aryl, aralkyl, and dialkylaminoalkyl radicals containing 1 to 8 carbon atoms and R and R together with the nitrogen atom form a heterocyclic radical selected from the group consisting of piper-idino, morpholino, pyrrolidino and piperazino.

2. 21-(N,N-dimethylaminomethyl)-allopregnane- 35,20,3-diol.

3. 2l-plperidinomethyl-allopregnane-3BJOfi-diol.

4. 21-morpholinornethyl-allopregnane-3fiJOQ-diol.

5 21-pyrroliclinomethyl-allopregnane-3 BJQB-diol.

6. 21-piperazinomethyl-allopregnane-3[3,20B-diol.

7. The dipropionate of 21 (N,N dimethylaminomethyl) -al1opregnane-3fl,20fi-diol.

8. The chlorohydrate of 2l-(N,N-dimethylaminomethyl)-allopregnane-3[3,2OB-diol.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FOLLOWING FORMULA: 